rs10849441

Positions:

• chr12-6326405-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384598.1(PLEKHG6):​c.1525-23A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 1,589,732 control chromosomes in the GnomAD database, including 166,781 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.40 (12926 hom., cov: 32)
  • Exomes 𝑓: 0.46 (153855 hom.)
• Consequence: PLEKHG6 NM_001384598.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.255

Genes affected

PLEKHG6 (HGNC:25562): (pleckstrin homology and RhoGEF domain containing G6) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in cell junction and centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLEKHG6	NM_001384598.1	c.1525-23A>G		intron_variant		ENST00000684764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLEKHG6	ENST00000684764.1	c.1525-23A>G		intron_variant			NM_001384598.1	P1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60251 AN: 151694 Hom.: 12919 Cov.: 32

Gnomad AFR AF: 0.246

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.411

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.582

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.484

Gnomad OTH AF: 0.378

GnomAD3 exomes AF: 0.414 AC: 102975 AN: 248920 Hom.: 22407 AF XY: 0.417 AC XY: 56189 AN XY: 134738

Gnomad AFR exome AF: 0.254

Gnomad AMR exome AF: 0.333

Gnomad ASJ exome AF: 0.406

Gnomad EAS exome AF: 0.254

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.456 AC: 655064 AN: 1437920 Hom.: 153855 Cov.: 28 AF XY: 0.454 AC XY: 325359 AN XY: 716776

Gnomad4 AFR exome AF: 0.238

Gnomad4 AMR exome AF: 0.332

Gnomad4 ASJ exome AF: 0.403

Gnomad4 EAS exome AF: 0.279

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.480

Gnomad4 OTH exome AF: 0.428

GnomAD4 genome AF: 0.397 AC: 60273 AN: 151812 Hom.: 12926 Cov.: 32 AF XY: 0.400 AC XY: 29658 AN XY: 74144

Gnomad4 AFR AF: 0.246

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.411

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.324

Gnomad4 FIN AF: 0.582

Gnomad4 NFE AF: 0.484

Gnomad4 OTH AF: 0.382

Alfa AF: 0.441 Hom.: 5367

Bravo AF: 0.370

Asia WGS AF: 0.303 AC: 1055 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.45
BranchPoint Hunter		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10849441; hg19: chr12-6435571; COSMIC: COSV50598978; COSMIC: COSV50598978;